The biochemical response to food intake must be precisely regulated. Because ingested sugars and fats can feed into many anabolic and catabolic pathways1, how our bodies handle nutrients depends on strategically positioned metabolic sensors that link the intrinsic nutritional value of a meal with intermediary metabolism. Here we describe a subset of immune cells—integrin β7+ natural gut intraepithelial T lymphocytes (natural IELs)—that is dispersed throughout the enterocyte layer of the small intestine and that modulates systemic metabolism. Integrin β7− mice that lack natural IELs are metabolically hyperactive and, when fed a high-fat and high-sugar diet, are resistant to obesity, hypercholesterolaemia, hypertension, diabetes and atherosclerosis. Furthermore, we show that protection from cardiovascular disease in the absence of natural IELs depends on the enteroendocrine-derived incretin GLP-12, which is normally controlled by IELs through expression of the GLP-1 receptor. In this metabolic control system, IELs modulate enteroendocrine activity by acting as gatekeepers that limit the bioavailability of GLP-1. Although the function of IELs may prove advantageous when food is scarce, present-day overabundance of diets high in fat and sugar renders this metabolic checkpoint detrimental to health.
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This work was supported by NIH grants R35 HL135752, R01 HL128264, P01 HL131478, the AHA EIA and the Patricia and Scott Eston MGH Research Scholar (to F.K.S.). S.H. was supported by an AHA Postdoctoral Award (16POST27250124); F.K. and W.C.P. by the German Research Foundation (DFG); S.R. was supported by a postdoctoral fellowship from the Swedish Research Council; M. Nairz was supported by a FWF Erwin Schroedinger Fellowship (J3486-B13); J.E.M. was supported by a NIH training grant (T32 AI118692); L.H. was supported by a Boehringer Ingelheim Fonds MD Fellowship; and D.J.D. was supported by a CIHR grant 154321, the Canada Research Chairs program and a BBDC-Novo Nordisk Chair in Incretin biology. We thank K. Joyes for copy-editing the manuscript.
Nature thanks D. Mucida, F. Reimann and the other anonymous reviewer(s) for their contribution to the peer review of this work.
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Nature Reviews Cardiology (2019)